Process for producing derivatives of pyrazine



Patented Aug. 17, 1948 PROCESS FOR PRODUCING DERIVATIVES OF PYRAZINE John Weijlard, Westfield, and Max Tishler, Rahway, N. J assignors to Merck & 00., Inc., Rahway, N. J a corporation of'New Jersey N Drawing.

2 Claims. (Cl. 260-250) This invention relates to processes for the production of pyrazine derivatives, and more particularly, it relates to the production of such derivatives from corresponding polynuclear compounds containing a lumazine nucleus.

The pyrazine derivatives with which the present invention is concerned are difricult' to prepare by processes heretofore available. The present invention is of great value, therefore, since it permits the preparationof such pyrazine derivatives in good yield, and by simple, economical procedures utilizing readily available and relatively inexpensive starting materials.

The polynuclear compounds which may be utilized as starting materials according to our invention are lumazine, substituted lumazines including monoand di-alkyl and monoand diphenyl substituted lumazines, and phenanthralumazine.

Diphenyl lumazine can be prepared by the process disclosed in the Journal of the Ind. Chem. Society, 14, 627 (1937); and phenanthralumazine can 'be prepared by the process disclosed in Berichte, 70, 761 (1937).

We have found that the pyrimidine ring in these polynuclear compounds may be hydrolytically split, by treatment thereof with an alkali metal hydroxide, in aqueous solution. Depending upon the conditions employed, the reaction prodnot thus obtained may comprise the alkali metal salts of 2-amino-3-carboxyl pyrazines, 2-hydroxy- B-carboxyl-pyrazines, or mixtures thereof.

Within the purview of our invention, and as a specific embodiment thereof, we have found that it is possible, when employing'lumazine, to control the reaction so that either the alkali metal salt of 2-amino-3-cariboxyl pyrazine, or the alkali metal salt of 2-hydroxy-3-carboxyl pyrazine is Application September 18,1943, Serial No. 502,966

obtained in practically quantitative yield, or in substantially preponderant amounts. According to our invention, the substantially selective production of either the alkali metal salt of 2-amino- 3-carboxyl pyrazine, or f2-hydroxy-3-carboxyl pyrazine, is achieved by controlling the amount of alkali metal hydroxide employed in the reaction;

Generally speaking, when an excess of alkali metal hydroxide is reacted with the polynu-clear compound, preponderant quantities of the alkali metal salt of 2-hydroxy-3-carboxyl pyrazineare produced, with correspondingly diminished quantities of the 2-amino-3-carboxyl pyrazine compound. Our invention, then, further comprises the determination of optimum conditions for the substantially selective production of either alkali metal salts of 2-amino-3-carboxyl pyrazine,'or of 2-hydroxy-3-carboxyl pyrazine.

The amount of alkali metal hydroxide to be used for the preferred production of the alkali metal salt of 2-amino-3-carboxyl pyrazine is pref erably in the neighborhood of from 1 to 3 mols of alkali metal hydroxide to one mol of lumazine.

Quantities of alkali metal hydroxide substantially in excess of 1-3 mols to one mol of lumazine tend to favor the production of larger amounts orf the alkali metal salt of 2-hydroxy-3-carboxyl pyrazine.

The table illustrates the results obtained by also the yield of crude and pure Z-amino pyrazine,

after decarboxylation, as well as the overall yield on the basis of lumazine.

TABLE Results obtained on treatinij one mol of lumazine with varying quantities of sodium hydroxide #1 #2 #3-4 H #5 #6 Yield 4 moles NaOH, 24 3.25 moles NaOH, 3.25 m'oles NaOH, 3.25 moles NaOH, 3.25 moles NaOH hours 170 0., Bomb 21 hrs. 170 0., 15-18 hrs. 170 0., 11 hrs. 170 0., 8 hrs. 170C as full Bomb 34; full Bomb ,6 full Bomb 6 full Bomb A full Per Cent Crude 89.0%, M. P. 192-194".

P Cent Crude 100% 85.3%,M.P.95

Amino Pyrazine.

Per Cent Pure 7.5%, M. P. 1l8l20 58.5%, M. P. ll8-l20 i Amino Pyrazine.

P r Cent Overall 6.8% 44.4%

Yield 0n Basis of Lumazine.

80.4%, M. P. l91l93 .so.3%, M. P. 95

Yield 3.11 moles NaOH, 3.11 moles NaOH, 2.82 moles NaOH, 2.00 moles NaOH, 2.25 moles NaOH,

2 hrs. 170 0., 2 hrs. 150 0., 2 hrs. 170 0., 8 hrs. 170 0., 4 hrs. 170 0., Bomb 36, full Bomb full Bomb full Bomb full Bomb %ful1 88.8%, M. P. ll8l20.

As will be observed from the table, the optimum amount of sodium hydroxide to be employed for the production of best yields of the sodium salt of 2-amino-3-carboxyl pyrazine from lumazine is about 2.8 mols per mol of lumazine. As the ratio of sodium hydroxide to lumazine is increased, the yield of the 2-amino-3-carboxyl pyrazine salt is correspondingly diminished. However, even at 4 mols of sodium hydroxide to one mol of lumazine, some sodium salt of v2-amino- 3-carboxyl pyrazine is obtained, although the reaction product comprises a preponderant amount of the sodium salt of 2-hydroxy-3-carboxyl pyrazine.

In the case of the substituted lumazines, which are more resistant to hydrolytic splitting, larger amounts of alkali metal hydroxide are required for the production of both the corresponding alkali metal salt of the 2-amino-3-carboxyl pyrazine and the 2-hydroxy-3-carboxyl pyrazines, generally in excess of 3 mols of alkali metal hydroxide to one mol of substituted lumazine being required for the production of the alkali metal salt of the 2-amino-3-carboxylpyrazine. Preferred conditions for the treatment of such substituted lumazines, according to our invention, will be apparent from the specific examples given below. 1

The hydrolytic splitting of the pyrimidine ring of polynuclear compounds containing the lumazine nucleus, according to our invention, may be carried out at atmospheric pressure, or at increased pressure. The temperature and time-oireaction conditions will vary depending upon the pressure employed,

After hydrolytic splitting of the pyrimidine ring has been effected, the reaction mixture containing the alkali metal salts of the 2-amino and/or 2-hydroxy-3-carboxyl pyrazines may be worked up in any suitable manner. The free acids may be recovered by adjusting the .pH of the reaction mixture to 2-3, and collecting the crystalline material obtained. It is also possible to obtain the free acids by converting the alkali metal salt to a barium salt, and then acidulating an aqueous suspension of such barium salt, as will appear from the various examples given herein.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

EXAMPLE I Hydrated lumazine, corresponding to 20 gms. of anhydrous material, is added to a solution of 11 gms. of sodium hydroxide in 80 cc. of water, and the mixture is heated in a steel bomb for eight hours at 170 C. The reaction mixture is acidulated with hydrochloric acid to pH 2.5, and chilled to 2 C. 2-amino3-carboxyl pyrazine crystallizes out. The crystals are collected and washed with ice Water. Yield, 15.85 gms.; M. P. 198 C.

This product may be further purified by dissolving it in boiling water, adjusting the .pH to 2.5 with hydrochloric acid, decolorizing, filtering, chilling, and washing and drying the crystals thus obtained. M. P. 201 C.

EXAMPLE II 3 gms. of crude 7-methyl lumazine are added to a solution of 6 gms. of sodium hydroxide in 30 cc. of water, and the mixture is boiled under reflux for 50 hours. The solution is diluted with 200 cc. of water, neutralized with hydrochloric acid, and made slightly ammoniacal. 10 cc. of 30% barium chloride solution are added, and the mixture is chilled at 2 C. for about 12 hours. The crystals are collected on a filter, washed with ice water, and dried in vacuo; yield, 2.50 gms. barium salt.

The barium salt is suspended in 200 cc. of water, 10 cc. of 10% hydrochloric acid are added, and the mixture is heated to boiling. After adding a little decolorizing black, the hot solution is filtered, then chilled at 2 C. for about 12 hours. Z-amino-3-carboxyl6-methy1 pyrazine crystallizes out. The crystals are washed with ice water and dried; yield, 0.95 gm. of 2-amino-3-carboxyl- 6-methyl pyrazine; M. P. 211 C.

EXAMPLE III 3 gms. of crude 6,7-dimethyl lumazine are added to a solution of 6 gms. of sodium hydroxide in 30 cc. of water, and the mixture is boiled under reflux for 50 hours. The mixture is worked up in accordance with the procedure described in Example II. Yield, 2.95 gms. of the barium salt of Z-amino-3-carboxyl-5,6-dimethyl pyrazine. From the barium salt, 1.10 gms. of 2-amino-3- carbOXyl-S'fi-dimethyl pyrazine are obtained. The product may be further purified by dissolving it in boiling water containing a small quantity of hydrochloric acid, chilling the clear solution, etc. 2-amino-3-carboxyl-5,6-dimethyl pyrazine of M. P. 209-210 C., with decomposition, is thus obtained.

EXAMPLE IV 3 gms. of crude 6,7-diphenyl lumazine are added to a solution of 6 gms. of sodium hydroxide in 30 cc. of water, and the mixture is boiled under reflux for 35 hours. An oily mass separates; the mass solidifies to a tough lump on cooling. The solution is decanted ofi, and the mass is washed with some ice Water and dried in vacuo. Yield; 2.8 gms. of crude sodium salt of 2-amino-3-carboxyl-5,6-diphenyl pyrazine. The sodium salt is dissolved in 30 cc. of Warm water, and the barium salt of 2-amino-3-carboxyl-5,6-diphenyl pyrazine is precipitated with barium chloride solution. Yield; 2.57 gms. The lbarium salt is suspended in 50 cc. of water, 1.0 cc. of 10% hydrochloric acid are added, the mixture is heated to C. andasuffi-cient amount of methanol (200 cc.) is added to dissolve the liberated compound. The hot solution is filtered, and diluted with four volumes of water.

2-amino-3-carboxyl-5,6-diphenyl pyrazine precipitates in the form of fine crystals, which arewashed EXAMPLE V 9 gms. of .phenanthralumazine are added to a solution of 9 gms. of sodium hydroxide in 75 cc. of water, and the mixture is held in a steel bomb at 225-235 C. for 20 hours. The reaction mixture is dissolved in 1000 cc. of boiling water, the solution is treated with some charcoal, filtered, and acidulated with hydrochloric acid to pH 2. 2-amino-3-carboxylphenanthrapyrazine precipitates in the form of bright yellow crystals, which are washed with water and dried at 80 C. Yield, 7.0 gms.; M. P. 219-221 C. The product may be further purified by dissolving it in aqueous sodium bicarbonate solution, decolorizing, reprecipitating with acid, and washingand drying the crystals thus obtained. M. P. 220-222 C.

EXAMPLE VI 2 gms. of 2-arnino-3-carboxyl pyrazine are dissolved in 20 cc. of 20% sodium hydroxide solution, and the mixture is heated in a steel bomb at 170 C. for 20 hours. The reaction mixture is diluted with 50 cc. of water and acidulated with hydrochlori-c acid to pH 2.5-3. 2-hydroxy-3-carboxyl pyrazine is obtained in the form of crystals, which are washed with ice water and dried. Yield, 1.62 gms.; M. P. 218-220 C. This product may be further purified by dissolving it in aqueous sodium bicarbonate solution, decolorizing, reprecipitating with acid, etc. The white compound thus obtained melts at 218-220 C.

EXAMPLE VII 125 gms. of lumazine are added to a solution of 122 gms. of sodium hydroxide in 600 cc. of water, and the mixture is heated at 170 C. for 24 hours in a bomb. The reaction mixture is diluted with water and acidulated with hydrochloric acid to a pH of 2.5 to 3. The crystals thus obtained are collected, washed with ice water, and dried. The 2-hydroxy-3-carboxyl pyrazine thus obtained may be further purified by dissolving it in aqueous sodium bicarbonate solution, decolorizing, reprecipitating with acid, and washing and drying the crystals thus obtained. Yield, 96.4 gms.;

91% of theory; M. P. 2l8-220 C.

EXAMPLE VIII 22.3 gms. of anhydrous 7-methyl lumazine and 24 gms. of sodium hydroxide in 140 cc. of water are heated at 170-175 C. for 20 hours in a steel bomb. The reaction mixture is made acid with hydrochloric acid (pH 2.5), and chilled to 2 C. for two hours. The crystals are collected and washed with x 10 cc. of ice water, then dried at 80 C. Yield of 2-amino-B-carboxyl-G-methyl pyrazine, 14.62 gms.; M. P. 211 C.

EXAMPLE IX 2.7 gms. of 6,7-dimethyl lumazine and 2.7 gms. of sodium hydroxide in 25 cc. of water'are heated at 170-175 C. in a steel bomb for hours. The reaction mixture is rinsed out of the bomb with cc. of hot water, made acid by hydrochloric acid (pH 2.5) and chilled to 2 C. for two hours.

. 6 The solid is collected on a filter, Washed with ice water, and dried at C. Yield of 2-amino-3- carboxyl-5,6-dimethyl pyrazine, 2.15 gms.; M. P. 210 C. y

In addition to the sodium hydroxide specifically recited in the foregoing examples, other alkali metal hydroxides-as for instance, potassium hydroxide, may likewise be employed with similar favorable results. i

This application is one of a series of applications upon related subject matter filed by applicants Weijlard and Tishler, and in one instance with another applicant. These concurrently filed applications are as follows: Serial No. 502,965,

r now abandoned, relates to the decarboxylation, by.

lates to cleavage of the pyrimidine ring of pyrimidopyrazines [by heating the same with an aqueous solution of alkali-metal hydroxide; Serial No. 502,967 relates to the process of Serial No. 502,966 (the instant case) and in addition embraces the recovery of the free amino-carboxy-pyrazines and their decarboxylation; Serial No. 502,968, now abandoned, relates to cleavage of the pyrimidine ring of alloxazine by heating with ammonium hydroxide, followed by acidification and decarboxylation; Serial No. 502,969, now abandoned, relates to the thermal decarboxylation of 2- amino-8-carboxy-pyrazines and/or 2-hydroxy-3- carboxy-pyrazines; Serial No. 502,970, now abandoned, relates to the pyrimidine-ring cleavage of pyrimidopyrazines by treatment with aqueous alkali-metal hydroxide inexcess to form alkalimetal salt of corresponding carboxy-pyrazines; and Serial No. 502,971, now Patent No. 2,431,896, relates to cleavage of the pyrimidine ring of pyrimido-pyrazines by heatingsame with concentrated sulfuric acid.

Modifications may be made in carrying out the present invention, without departing from the spirit and scope thereof, and we are to [be limited only by the appended claims.

' We claim:

1. The process that comprises heating one molar equivalent of lumazine and 1 to 8 molar equivalents of an alkali metal hydroxide in aqueous solution under pressure at a temperature of 150- '170 C. for 2 to 8 hours thereby forming the corresponding alkali metal salt of 2-amino-3-carboxyl pyrazine, and adjusting the pH of the reaction mixture to about 2-3 to form 2-amino-3- carboxyl pyrazine.

2. The process that comprises heating one molar equivalent of lumazine and 1 to 3 molar equivalents of sodium hydroxide in aqueous solution under pressure at a temperature of 150-170 C. for 2 to 8 hours thereby forming the sodium salt of 2-amino-3-carboxyl pyrazine, and adjusting the pH of the reaction mixture to about 2-3 to form 2-amino-3-carboxyl pyrazine.

JOHN WEIJLAR MAX TISHLER.

REFERENCES CITED The following references are of record in the file of this patent:

Chemical Abstracts, vol. 8, pages -126 (1914); ibid., vol. 28, page 5070 (1934).

Ber. der Deu. Chem., vol. 40, pages 4850-60; ibid., vol. 6'7-B, pages 892-908 (1934); ibid., V01. 70, pages 761-768 (1937).

Beilstein, vol. 26, 4th edition, page 493, 

